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Tucker and Bailey's paper

Bailey Johnson
Research Paper
Dr. Robson
March 10th, 2009
Hemophilia: It Just Doesn’t Stop
Intro
When Jack turned nine years old, his parents decided it was time to tell him the details concerning his disorder. Jack knew the basics; when he would get a bruise around a joint it would be extra painful and swell, find blood in his urine, and get extra attention paid to him when he would inflict a small laceration that none of the other kids at school seemed to receive. His parents sat him down and began describing the general idea of the disorder. They explained hemophilia is a blood disorder that is inherited. It is not very common, about 400 babies are born with it a year. Jack pondered the brief explanation while several questions arose in his mind. The first question that came out of his mouth was, “What is hemophilia?”
Body
The major types of this condition are hemophilia A, classic hemophilia, and hemophilia B, Christmas disease. Although the two types have very similar signs and symptoms, they are caused by mutations in different genes. There are also different forms of these types, for example, hemophilia B Leyden (1). This form causes episodes of excessive bleeding in childhood, but few bleeding problems after puberty. Mutations for hemophilia are found on F8 and F9 genes. Changes in F8 genes correspond to hemophilia A, while mutations in F9 gene cause hemophilia B. The F8 gene provides instructions for making a protein called coagulation factor VIII. A related protein, coagulation factor IX, is produced by F9 gene (1). Coagulation factors are proteins that work together in the clotting process. After a laceration, blood clots protect the body by sealing off damaged blood vessels and preventing continued blood loss. Mutations in the F8 and F9 genes still allow for the production of the proteins, but the proteins produced are slightly altered. The mutated coagulation factors can not participate effectively in blood clotting and cause excessive bleeding that is not easily controlled. The severity of symptoms can vary. Severe forms become apparent early on. Bleeding is the main symptom of the disease and sometimes, though not always, occurs if an infant is circumcised (2). Additional bleeding problems are seen when the infant starts crawling and walking. Mild cases may go unnoticed until later in life when they occur in response to surgery or trauma. Internal bleeding may happen anywhere, and bleeding into joints is common. Risk factors are a family history of bleeding and being male. Rarely, adults can develop a bleeding disorder similar to hemophilia A. This may happen after giving birth (post partum), in people with certain autoimmune diseases such as rheumatoid arthritis, in people with certain types of cancer (most commonly lymphomas and leukemias), and also for unknown reasons (called "idiopathic"). Although these situations are rare, they can be associated with serious, even life-threatening bleeding (2).
Hemophilia A and B are inherited in an X-linked recessive pattern. This means that it is only apparent on the X chromosome, and since males only have one, the chance of getting and X linked disorder is more common. One altered copy is sufficient enough to cause the condition; females need two altered copies, in each of their X chromosomes. Carrier females have a 50% chance of transmitting the mutated gees in each pregnancy. Sons who inherit the mutation will be affected, but daughters who do are carriers. Affected males transmit the mutation the all of their daughters and none of their sons. Genetic counseling can identify the mutation in a family member.
Although, a complete diagnosis of hemophilia can not be found through clinical testing, there are three main types of clinical testing of hemophilia. Targeted mutation analysis is used to locate an F8 intron 22 gene. This inversion can be detected my southern blotting or, more recently, by long-range or inverse PCR. Mutation scanning can detect gross gene alterations, including large deletions or insertions, frameshift and splice junction changes (3). Deletion analysis is available to detect exonic, multiexonic, or lager deletions in affected males and potential carrier females. If clinical tests are not conclusive, a coagulation disorder may be present in an individual experiencing the following: Hemarthrosis, especially with mild or no antecedent trauma, deep-muscle hematomas, intracranial bleeding in the absence of major trauma, INeonatal cephalohematoma or intracranial bleeding, prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision, prolonged bleeding or renewed bleeding following surgery or trauma, unexplained GI bleeding or hematuria, menorrhagia, especially at menarche, prolonged nosebleeds, especially recurrent and bilateral, excessive bruising, especially with firm, subcutaneous hematomas (4).
Standard treatment involves replacing the missing clotting factor. The amount of factor VIII concentrates needed depends on how severe the bleeding is, the site of the bleeding, and the size of the patient. Mild hemophilia may be treated with desmopressin (DDAVP), which helps the body release factor VIII that is stored within the lining of blood vessels. To prevent a bleeding crisis, people with hemophilia and their families can be taught to give factor VIII concentrates at home at the first signs of bleeding. People with severe forms of the disease may need regular preventative treatment. Depending on the severity of the disease, DDAVP or factor VIII concentrate may be given before having dental extractions and surgery to prevent bleeding. Immunization with Hepatitis B vaccine is necessary because of the increased risk of exposure to hepatitis due to frequent blood infusions. Patients who develop an inhibitor to factor VIII may require treatment with other clotting factors such as factor VIIa, which can help with clotting even without any factor VIII.
With treatment, the outcome is good. Most people with hemophilia are able to lead relatively normal lives. A small percentage of people with hemophilia will develop inhibitors of factor VIII, and may die from loss of blood. People with hemophilia A should establish regular care with a hematologist (blood doctor), especially a doctor who is associated with a hemophilia treatment center. The ability to have quick and easy access to medical records documenting the level of Factor VIII that the person has had, the history of factor transfusions (including the types and amounts), any complications, and the type and amount of any inhibitors can be lifesaving in the event the person with hemophilia is in an emergency situation.
Now, moving on to the molecular level of this disorder or the” juicy part”. In normal allelic variants, he normal F8 gene spans 186 kb and contains 26 exons. Normal variants are uncommon in the factor VIII transcript. Normal allelic variants that are useful for linkage analysis include: a restriction site in intron 18, a single base change in intron 7, a site in intron 22, a site in intron 25, a dimorphism at a Msel site in the 3’ untranslated portion of exon 26 and a specific base and two series of repeat polymorphisms in introns 13 and 22.
In normal gene production, factor VII is expressed with a 19 amino acid signal peptide. The mature protein has residues. Its domain structure from the amino terminus is homologous to clotting factor V. Factor VII is synthesized primarily in the liver and circulates as an inactive clotting cofactor that has variably cleaved towards the carboxy terminus of the B domain prior to secretions. Concentration in the plasma is just under 1 nmol/L. In the circulation, factor VII is stabilized by binding to von Willebrand factor (VWP). Once activated by trace amounts of thrombin, it is released from VWF and binds to phospholipids membrane surfaces such as those provided by activated platelets.
Conclusion
Hemophilia can sometimes lead to death if it is not maintained correctly. The most common type of death by bleeding in usually intracranial and can be caused by a blunt blow to the head….Go into discussion about major points

Still to add: Experimental evidence, how results shape current understanding, types of experiments done, add table of collected data…..